European Patent Application No. 0 420 396 A2 (Smith Kline & French Laboratories Limited) and Howson et al., Bioorg. & Med. Chem. Letters, Vol. 2 No. 1 (1992), pp. 77-78 describe imidazole derivatives having an amidine group as H.sub.3 agonists. Van der Groot et al. (Eur. J. Med. Chem. (1992) Vol. 27, pp. 511-517) describe isothiourea analogs of histamine as potent agonists or antagonists of the histamine H.sub.3 receptor, and these isothiourea analogs of histamine overlap in part with those of the two references cited above. Clapham et al. ["Ability of Histamine H.sub.3 Receptor Antagonists to improve Cognition and to increase Acetylcholine Release in vivo in the Rat", British Assn. for Psychopharmacology, Jul. 25-28 1993, reported in J. Psychopharmacol. (Abstr. Book), A17] describe the ability of histamine H.sub.3 receptor antagonists to improve cognition and to increase release of acetylcholine in vivo in the rat. Clapham et al. ["Ability of the selective Histamine H.sub.3 Receptor Antagonist Thioperamide to improve Short-term Memory and Reversal Learning in the Rat", Brit. J. Pharm. Suppl., 1993, 110, Abstract 65P] present results showing that thioperamide can improve short-term memory and reversal learning in the rat and implicate the involvement of H.sub.3 receptors in the modulation of cognitive function. Yokoyama et al. ["Effect of thioperamide, a histamine H.sub.3 receptor antagonist, on electrically induced convulsions in mice", Eur. J. Pharmacol., vol. 234 (1993), pp. 129-133] report how thioperamide decreased the duration of each phase of convulsion and raised the electroconvulsive threshold, and go on to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures. International Patent Publication No. WO9301812-A1 (SmithKline Beecham PLC) describes the use of S-[3-(4(5)-imidazolyl)propyl]isothiourea as a histamine H.sub.3 antagonist, especially for treating cognitive disorders, e.g. Alzheimer's disease and age-related memory impairment. Schlicker et al. ["Novel histamine H.sub.3 receptor antagonists: affinities in an H.sub.3 receptor binding assay and potencies in two functional H.sub.3 receptor models"] describe a number of imidazolylalkyl compounds wherein the imidazolylalkyl group is bonded to a guanidine group, an ester group or an amide group (including thioamide and urea), and compare these to thioperamide. Leurs et al. ["The histamine H.sub.3 -receptor: A target for developing new drugs", Progr. Drug Res. (1992) vol.39, pp.127-165] and Lipp et al. ["Pharmacochemistry of H.sub.3 -receptors" in The Histamine Receptor, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pp.57-72] review a variety of synthetic H.sub.3 receptor antagonists, and Lipp et al. (ibid.) have defined the necessary structural requirements for an H.sub.3 receptor antagonist.
WO 95/14007 claims H.sub.3 receptor antagonists of the formula ##STR2## wherein A is selected from --O--CO--NR.sup.1 --, --O--CO--, --NR.sup.1 --CO--NR.sup.1 --, --NR.sup.1 --CO--, --NR.sup.1 --, --O--, --CO--NR.sup.1 --, --CO--O--, and --C(:NR.sup.1)--NR.sup.1 --;
the groups R.sup.1, which may be the same or different when there are two or three such groups in the molecule of formula I, are selected from hydrogen, and lower alkyl, aryl, cycloalkyl, heterocyclic and heterocyclylalkyl groups, and groups of the formula --(CH.sub.2).sub.y --G, where G is selected from CO.sub.2 R.sup.3, COR.sup.3, CONR.sup.3 R.sup.4, OR.sup.3, SR.sup.3, NR.sup.3 R.sup.4, heteroaryl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhaloloweralkyl, and y is an integer from 1 to 3; PA1 R.sup.2 is selected from hydrogen and halogen atoms, and alkyl, alkenyl, alkynyl and trifluoromethyl groups, and groups of the formula OR.sup.3, SR.sup.3 and NR.sup.3 R.sup.4 ; PA1 R.sup.3 and R.sup.4 are independently selected from hydrogen, and lower alkyl and cycloalkyl groups, or R.sup.3 and R.sup.4 together with the intervening nitrogen atom can form a saturated ring containing 4 to 6 carbon atoms that can be substituted with one or two lower alkyl groups; PA1 with the proviso that, when y is 1 and G is OR.sup.3, SR.sup.3 or NR.sup.3 R.sup.4, then neither R.sup.3 nor R.sup.4 is hydrogen; PA1 the group --(CH.sub.2).sub.n --A--R.sup.1 is at the 3- or 4-position, and the group R.sup.2 is at any free position; PA1 m is an integer from 1 to 3; PA1 and n is 0 or an integer from 1 to 3; PA1 or a pharmaceutically acceptable acid addition salt thereof; PA1 or a pharmaceutically acceptable salt thereof with a base when G is CO.sub.2 H; including a tautomeric form thereof. PA1 each R.sup.1 is independently selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, phenyl and benzyl; PA1 each R.sup.7 is independently selected from the group consisting of hydrogen, lower alkyl, halogen, trihalomethyl, NR.sup.10 R.sup.11, or a group OR.sup.10, whereby R.sup.10 and R.sup.11 are independently selected from hydrogen, lower alkyl or trihalomethyl; PA1 X is --CONR.sup.5 --; --SO.sub.2 --, --S--; --CO--; --COO--; --CN(OR.sup.5)NR.sup.5 --; --C(NR.sup.5)NR.sup.5 --; --SONR.sup.5 --; --SO.sub.2 NR.sup.5 -- and, provided p is not zero, X may also be --O--; --NR.sup.5 --; --NR.sup.5 CONR.sup.5 --; --OCONR.sup.5 --; --O--CO-- or --NR.sup.5 CO--; PA1 Y is C.sub.1 -C.sub.3 -alkyl, optionally substituted at any carbon atom of the group by one substituent R.sup.5 ; PA1 Z is C(R.sup.1).sub.2 ; wherein no more than two R.sup.1 groups are other than hydrogen; PA1 n is 1 or 2; PA1 m is 0 or 1; PA1 p is 0 or 1; PA1 q is 0 or 1; PA1 R is selected from C.sub.3 to C.sub.7 cycloalkyl, heterocyclic groups, aryl or heteroaryl, wherein said R groups are optionally substituted with 1-3 substituents as defined below; PA1 each R.sup.5 independently represents hydrogen, lower alkyl or poly-haloloweralkyl; and PA1 R.sup.15 represents H or lower alkyl (e.g., methyl). PA1 lower alkyl (including the alkyl portions of lower alkoxy)--represents a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms, preferably from 1 to 4; PA1 aryl--represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with 1 to 3 groups, each optional substituent being independently selected from the group consisting of lower alkyl, halogen, trihalomethyl, CN, NO.sub.2, OR.sup.10 or NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, lower alkyl or trihalomethyl; preferred aryl groups include 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl; PA1 cycloalkyl--represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, optionally substituted by 1 to 3 groups independently selected from the group consisting of lower alkyl trihalomethyl and NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, lower alkyl or trihalomethyl; said cycloalkyl group optionally being fused to an aryl ring (e.g., phenyl), e.g., cyclohexyl fused to phenyl; PA1 heterocyclic--represents saturated and unsaturated non-aromatic cyclic organic groups having at least one O, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms; e.g., 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl; said heterocyclic group being optionally substituted by 1 to 3 groups independently selected from the group consisting of lower alkyl, trihalomethyl, and NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, lower alkyl or trihalomethyl, said substituents being bound to carbon atoms (substitutable carbon atoms) in the ring such that the total number of substituents in the ring is 1 to 3; and wherein said heterocyclic ring contains nitrogen atoms, said nitrogen atoms (i.e., the substitutable nitrogen atoms) being optionally substituted with lower alkyl (e.g., alkyl), e.g., 1-N-methylpyrrolidinyl; PA1 halogen--represents fluorine, chlorine, bromine and iodine; and PA1 heteroaryl--represents a cyclic organic group having at least one O, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., indolyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, and the like; preferred heteroaryl groups are 2-, 3- and 4-pyridyl; said heteroaryl groups being optionally substituted with 1 to 3 groups, each optional substituent being independently selected from the group consisting of lower alkyl, halogen, trihalomethyl, CN, NO.sub.2, OR.sup.10 or NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from hydrogen, lower alkyl or trihalomethyl, said substituents being bound to carbon atoms (substitutable carbon atoms) in the ring such that the total number of substituents in the ring is 1 to 3.
U.S. application Ser. No. 08/689951 filed Aug. 16, 1996 (now abandoned) and U.S. application Ser. No. 08/909319 filed Aug. 14, 1997 (now U.S. Pat. No. 5,869,479 issued Feb. 9, 1999) disclose compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H.sub.1 receptor antagonist and at least one histamine H.sub.3 receptor antagonist.
In view of the art's interest in compounds which affect the H.sub.3 receptors, novel compounds having antagonist activity on H.sub.3 receptors would be a welcome contribution to the art. This invention provides just such a contribution by providing novel compounds having H.sub.3 antagonist activity.